This invention relates to a process for preparing derivatives of prostanoic acid, in particular 9,15-dioxygenated derivatives of prostanoic acid and prost-13-enoic acid, related additionally unsaturated derivatives, to homologs thereof, and to intermediates used in their preparation.
The preparation of derivatives of prostanoic acid has become of great importance since the demonstration of the highly interesting biological activities of the natural prostaglandins, see e.g. Bergstrom, Abstracts International Congress of Biochemistry, Vol. 7, p. 559 (1964). Several synthetic methods for the preparation of 9,15-dioxygenated derivatives of prostanoic or prost-13-enoic acids have been described. For example, Bagli and Bogri in U.S. Pat. No. 3,432,541 issued Mar. 11, 1969, have described a 14-step process for preparing 9.zeta. ,15.zeta. -dihydroxyprost-13-enoic acid (11-desoxyprostaglandin F.sub.1) from cyclopentanone ethyl carboxylate and ethyl bromoheptanoate in which the unsaturated side chain was built up stepwise from the corresponding 3-carboxylic acid chloride. A significant simplification of that process was described by Bagli and Bogri in U.S. Pat. No. 3,455,992 issued July 15, 1969, in which the unsaturated side chain was introduced by reaction of the chloride of 2-(6-carbomethoxyhexyl)cyclopentan-1-one-3-carboxylic acid, obtained as described in U.S. Pat. No. 3,432,541, with the appropriate alkyne to obtain the corresponding unsaturated chloroketone, from which 9.zeta. ,15.zeta.-dihydroxyprost-13-enoic acid as well as homologs thereof are obtained by transformation of the chloro substituent to an oxygen function and removal of the keto group with concomitant dehydration.
A further improvement in the synthesis of 9,15-dioxygenated derivatives of prostanoic acid has been described by Bagli and Bogri in Tetrabedron Letters 1639 (1969). The oxygen-containing side-chain was introduced by treating 2-(6-carbomethoxyhexyl)cyclopent-2-en-1-one, prepared as described in U.S. Pat. No. 3,432,541, with an alkyl chlorovinyl ketone, with irradiation by means of a mercury vapour lamp, to obtain the intermediate 7-alkanoyl-6-chloro-2-oxobicyclo[3,2,0]-heptane-1-heptanoic acid methyl ester. Treatment of the latter compound with zinc and acetic acid gave 9,15-dioxoprostanoic acid methyl ester and homologs thereof, from which a number of other 9,15-dioxygenated derivatives of prostanoic acid and of homologs thereof were prepared by conventional means. It should be noted that this method permits only the obtention of compounds with a saturated oxygen-containing side-chain. However, it is particularly noteworthy that in all the processes described above the acidic side-chain and the oxygen-containing side-chain are in the trans configuration characteristic for the natural prostaglandins, and that the synthetic compounds described above possess a number of the biological activities of the natural compounds although they lack the 11-hydroxy group of the latter.
Other synthetic processes in this field have been summarized by Axen and Smissman, and by Bagli, in Annual Reports in Medicinal Chemistry, 290 (1967) and 170 (1969), respectively. While some of those processes have been useful in the laboratory, none of them have so far gained industrial importance. It is the object of this invention to provide a simple, economical and efficient process for the synthesis of 9,15-dioxygenated derivatives of prostanoic or prost-13-enoic acids, related additionaly unsaturated derivatives and homologs thereof which permits their preparation on a large scale.
In the following the terms "lower alkyl" will denote straight or branched alkyl groups containing from 1 - 3 carbon atoms and straight alkyl chains containing from 4-6 carbon atoms and include methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl; in accordance with the definition of n as an integer of from 1-6, the terms "3-oxoalk-1-enyl", "3-oxoalk-1-yl", "3-hydroxyalk-1-enyl" and "3-hydroxyalk-1-yl" denote straight alkyl or alkenyl chains substituted with the appropriate oxygen function in position 3 and containing from 5-10 carbon atoms, the term "2-oxoalkyl" used in connection with the Wittig reagent denotes straight alkyl chains having a ketonic oxygen in position 2 and containing from 4-9 carbon atoms, and the term "tetrahydropyranyl" will denote a tetrahydropyran-2-yl radical.
In the following the symbol Y as used herein represents a divalent radical of formula CH.sub.2 --(a)--(CH.sub.2).sub.m in which (a) is CH.sub.2 CH.sub.2, CH.dbd.CH or C.tbd.C and n is an integer from 2 - 4 carbon atoms.